论文标题

知识驱动的机械富集先兆子痫无知组

Knowledge-Driven Mechanistic Enrichment of the Preeclampsia Ignorome

论文作者

Callahan, Tiffany J., Stefanski, Adrianne L., Kim, Jin-Dong, Baumgartner Jr., William A., Wyrwa, Jordan M., Hunter, Lawrence E.

论文摘要

子痫前期是孕产妇和胎儿发病率和死亡率的主要原因。目前,先兆子痫的唯一明确治疗方法是胎盘的递送,胎盘是该疾病发病机理的核心。已广泛执行了先兆子痫的妊娠复杂妊娠的转录分析,以鉴定差异表达的基因(DEGS)。在实验上研究DEG的决定会受到许多因素的偏见,导致许多DEGS仍未进行研究。一组与疾病在实验上相关的DEG,但在文献中尚无与该疾病相关的DEG,被称为无知组。先兆子痫具有广泛的科学文献,大量的DEG数据,只有一种确定的治疗方法。促进基于知识的分析的工具,能够结合来自许多来源的不同数据以提出基本的行动机制,可能是支持发现并提高我们对这种疾病的理解的宝贵资源。在这项工作中,我们演示了如何使用生物医学知识图(KG)来识别新型的先兆子痫分子机制。现有的开源生物医学资源和公开可用的高通量转录分析数据用于识别和注释当前未经资助的先兆子痫相关的DEG的功能。使用文本挖掘方法从PubMed摘要中鉴定出与先兆子痫相关的基因。文本媒介和荟萃分析衍生的列表的相对补体被确定为未经投票的前启示性脱位相关的DEG(n = 445),即先前的无知组。使用kg研究相关的DEG,发现53种新型临床相关和生物学作用的机理关联。

Preeclampsia is a leading cause of maternal and fetal morbidity and mortality. Currently, the only definitive treatment of preeclampsia is delivery of the placenta, which is central to the pathogenesis of the disease. Transcriptional profiling of human placenta from pregnancies complicated by preeclampsia has been extensively performed to identify differentially expressed genes (DEGs). The decisions to investigate DEGs experimentally are biased by many factors, causing many DEGs to remain uninvestigated. A set of DEGs which are associated with a disease experimentally, but which have no known association to the disease in the literature are known as the ignorome. Preeclampsia has an extensive body of scientific literature, a large pool of DEG data, and only one definitive treatment. Tools facilitating knowledge-based analyses, which are capable of combining disparate data from many sources in order to suggest underlying mechanisms of action, may be a valuable resource to support discovery and improve our understanding of this disease. In this work we demonstrate how a biomedical knowledge graph (KG) can be used to identify novel preeclampsia molecular mechanisms. Existing open source biomedical resources and publicly available high-throughput transcriptional profiling data were used to identify and annotate the function of currently uninvestigated preeclampsia-associated DEGs. Experimentally investigated genes associated with preeclampsia were identified from PubMed abstracts using text-mining methodologies. The relative complement of the text-mined- and meta-analysis-derived lists were identified as the uninvestigated preeclampsia-associated DEGs (n=445), i.e., the preeclampsia ignorome. Using the KG to investigate relevant DEGs revealed 53 novel clinically relevant and biologically actionable mechanistic associations.

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